Project Summary/Abstract. We propose four interrelated subprojects to define the biomechanics of the eye rotating (extraocular) muscles (EOMs) and optic nerve (ON) in health and disease, understand novel EOM actions, and characterize effects of partial nerve damage to EOMs. This effort is to improve diagnosis and surgical treatment of strabismus, the misalignment of the directions of the two eyes, and glaucoma, a blinding disease due to progressive ON damage. We also propose a novel and critical nexus linking the EOMs and ON. Aim I will clarify in humans the way that regions of individual EOMs can prevent strabismus by compensating for alignment imbalances, testing by magnetic resonance imaging (MRI) of EOM function the differential compartmental hypothesis for their actions. MRI will be performed during fusional vergence in normal subjects, and in patients able to control common forms of horizontal and vertical strabismus by enhanced vergence mechanisms that might, if understood, be augmented by therapeutic means. Clarification of this vergence behavior is fundamental to understanding all ocular motility. Aim II will characterize effects of partial damage to EOM motor nerves to investigate microscopically the recent discovery on clinical imaging that several common forms of strabismus may be caused by disease in only one compartment of an individual EOM, sparing function in the other compartment. Knowledge of the degree to which denervation is locally confined in EOMs and their brainstem motor nuclei could improve strabismus diagnosis, and provide a basis for nuanced targeting of surgical therapy only to the diseased compartment. Aim III will define the quantitative effect of the ON sheath both as a biomechanical factor in ocular rotation and alignment, and a source of mechanical deformation of the optic disc and scleral eye wall. The constitutive viscoelastic, anisotropic properties of the non-muscular ocular tissues will be determined using modern engineering techniques in bovine, and normal and glaucomatous human post-mortem specimens, then combined into finite element analysis (FEA) models suitable for computational simulation to predict local mechanical strains in the ON and sclera that may cause glaucoma, as well as the ocular deformations underlying extreme nearsightedness. Aim IV will characterize by multipositional MRI the contributions of EOM forces to visual loss in patients with normal tension glaucoma, a common, blinding disease that we propose is mainly due to mechanical damage to the ON transmitted from the EOMs via the ON sheath during large and rapid eye rotations. We propose that intraocular pressure plays little or no role in this form of glaucoma. MRI in groups of patients with low and high pressure glaucoma will be compared with matched controls, and with FEA calculations in individual cases of mechanical strains on their ONs. FEA simulations will then test the plausibility that medical and surgical manipulations of EOMs and other orbital tissues could reduce mechanical strain on the ON, potentially abating a major cause of blinding glaucoma and high myopia.